Disease mechanism and pharmacological approaches for the CMT3 causing mutationSer72Leu in PMP22

Charcot Marie Tooth (CMT) neuropathies are a group of rare disorders of the peripheral nervous system that affects the development and the integrity of myelin, the fatty sheath surrounding the nerves. Although many disease genes have been identified for neuropathies, how disease is caused is poorly understood, and there is no effective treatment. For example, the mechanisms underlying severe dysmyelination and axonal degeneration (the basis of patients’ disability) in demyelinating CMT are still unknown. Some mutations in the peripheral myelin protein 22 (PMP22) such as the substitution of a Serine in position 72 of the aminoacidic sequence with a Leucine (PMP22-Ser72Leu) causes a particularly severe form of CMT known as CMT3 or Dejerine-Sottas syndrome. Recent studies from our group and others, suggest that PMP22 mutations that cause DSS may alter the protein trafficking inside the cell and cause the activation of cellular stress response pathways. The activation of these pathway may on one side limit protein toxicity, but on the other it may alter cellular proliferation and differentiation. In order to understand these mechanisms, and to envisage a therapeutic treatment, we study cellular systems that partially reproduce the human disease. These cellular systems can be exploited to further analyse this pathway and to investigate how its genetic and pharmacological modulation may improve the disease outcome with the final goal to treat hereditary neuropathies including DSS/CMT3. In parallel the clinical evaluation of patients with the Ser72Leu mutation will help in better dissecting progression and molecular signature of disease.